A growing list of viral pathogens and emerging infectious diseases are characterized by a pathology in human that involves hemorrhaging or vascular leakage. These, including Ebola, Marburg, Hanta, West Nile, etc., are among the most deadly human pathogens and currently there are no approved treatments to prevent virus-induced bleeding in infected patients. As one example, millions of individuals are infected yearly with Dengue Virus (DENV), and some of these develop potentially deadly disease states, such as Dengue Hemorrhagic Fever (DHF) of Dengue Shock Syndrome (DSS), both of which involve increases in vascular permeability and hemorrhaging within internal organs. In severe cases, circulatory failure and death can occur. Currently, no targeted treatments exist to stabilize the vasculature during severe DENV complications, in part due to the current lack of understanding of the mechanisms of DENV-induced vascular leakage. Although the vascular leakage associated with DHF and DSS can result in death, a more common form of DENV infection is Dengue fever with limited morbidity. As there are currently no clinical tests to distinguish between the mild and more severe forms of DENV infections, in some settings, all patients are managed as if they have the severe form of the infection, which is unproductive and expensive, especially in endemic areas in the world. In other cases, individuals with DENV are not brought to the hospital or are released from the hospital, and do not have access to proper medical care when their disease becomes severe and life-threatening.
Mast cells (MC) are cellular regulators of vascular integrity, tone and function. They line blood vessels and produce many vasoactive mediators that have redundant functions in inducing vascular permeability. Some of these MC products are pre-stored and can act nearly instantaneously on vascular endothelium, including TNF, proteases (e.g., chymase and tryptase), and heparin. Other de novo synthesized vasoactive factors include leukotrienes, prostaglandins, VEGF, and TNF. With their activation, MC-derived factors act in concert to promote the breakdown of junctions between endothelial cells, leading to plasma leakage and edema within tissues, as well as to reduce clot formation and increase blood flow in the vicinity of MC-activated endothelium. Systemic or aberrant activation of MCs is a contributing factor to many pathological conditions associated with leakage of blood vessels, including anaphylaxis, asthma, aneurysm and others. Severe DENV outcomes in human patients have been epidemiologically associated with high levels of vasoactive factors that MCs produce, high levels of products that enhance MC responses, including IgE and MC-activation associated symptoms, such as rash and thrombocytopenia.
Several of the infectious diseases that are characterized by hemorrhaging in a subject have different disease states. Such states may be characterized as mild (i.e., exhibits non-life threatening symptoms) and severe (i.e., exhibit life-threatening symptoms). An example of this are those individuals who are infected with Dengue Virus (DENV), where some individuals exhibit non-life threatening symptoms such as fever, headache, muscle and/or joint pains, skin rash, etc. (i.e., mild) and other who progress to Dengue Hemorrhagic Fever (DHF) which includes life-threatening symptoms such as bleeding, low levels of blood platelets, and blood plasma leakage, or Dengue Shock Syndrome (DSS) which includes dangerously low blood pressure. Unfortunately, there currently are no clinical tests to distinguish between the mild and more severe forms of these kinds of infections. In addition, there are no targeted treatments to stabilize the vasculature during severe DENV infection. Furthermore, there are no clinical tests to distinguish between the mild and more severe forms of DENV infections. Accordingly, there is a need for compositions and methods for the prevention and treatment of MC-mediated vascular leakage in conditions such as DENV. Further, there exists a need for methods that can distinguish between mild and severe forms of infectious diseases, such as DENV.